A
novel technique that helps the patient’s own immune system find and
destroy cancer cells could extend remission times for patients with B
cell lymphomas and leukemias.

This technique uses a gene transfer approach known as Sleeping Beauty
to create chimeric antigen receptors (CARs) for use in adoptive T cell
transfer and is being used in clinical trials at The University of
Texas MD Anderson Cancer Center.

Adoptive T cell transfer

Adoptive T cell transfer is a powerful innovation for the treatment of
lymphoma and leukemia. The theory behind the treatment is that T cells
harvested from the patient or a donor can be specifically targeted to
cancer cells by altering the T cells’ antigen receptors, which
recognize pathogens and cells as foreign or dysfunctional. The modified
T cells could effectively eliminate the cancer with minimal risk of
side effects.

Unmodified native T cells generally do not attack cancer cells, which
is one reason cancer cells can survive in a patient. Therefore, to make
adoptive T cell transfer successful, doctors must somehow alter the T
cells’ antigen receptors to ensure that the cells actively target and
kill the patient’s cancer cells. For B cell malignancies, these CARs
usually target CD19, a B cell–specific protein.

The traditional method of making CARs is to use viral transfection to
modify the T cells’ antigen receptors. After the antigen receptors are
modified, the chimeric T cells are cultured with antigen-presenting
cells that express CD19. These antigen-presenting cells stimulate the
transformed T cells and cause them to proliferate. Unfortunately, the
traditional viral method of creating CAR T cells is often expensive.

The Sleeping Beauty method

Recently, however, researchers led by Laurence Cooper, M.D., Ph.D., a
professor in the Division of Pediatrics, developed a less expensive,
nonviral method of creating CARs for patients. The method is called
Sleeping Beauty because it relies on a reconstructed version of a
transposon (a DNA sequence that can change its location within the
genome) that was present millions of years ago in the last common
vertebrate ancestor. The reconstructed transposon system can integrate
DNA into the host genome without a viral vector.

In this new system, the doctors identify a tumor-specific antigen or
marker, such as CD19, which they use to manufacture a CAR-containing
DNA construct specific to a patient’s cancer. The doctors insert that
sequence into a Sleeping Beauty–specific DNA plasmid. Then, instead of
using viruses to introduce the DNA to the T cells, the doctors use
electroporation, which disrupts the T cells’ membranes long enough for
the Sleeping Beauty DNA to be taken up by the T cells.

Clinical applications

Adoptive T cell transfer therapy typically is done after standard
treatment for lymphoma or leukemia. The patient’s T cells are usually
harvested before lymphoma or leukemia treatment begins. Depending on
the nature of the patient’s disease, such treatment may include
chemotherapy, immunotherapy, and/or targeted drugs and may be followed
by a hematopoietic stem cell transplant to help control residual
disease.

“Many drug companies are not in a financial position to pay attention to pediatric needs.... But we may be able to use CAR T cells as drugs in this group of vulnerable patients.”

– Dr. Laurence Cooper

While these therapies are occurring, the CAR construct is engineered
and inserted into the patient’s previously harvested T cells. When the
patient’s condition has stabilized after therapy, the patient receives
CAR-bearing T cells. Partow Kebriaei, M.D., an associate professor in
the Department of Stem Cell Transplantation, said, “Delivering CAR T
cells after transplantation targets minimal residual disease in hopes
of maintaining remission for people with high-risk B cell
malignancies.”

Dr. Kebriaei is the principal investigator for two of the three
first-in-human clinical studies at MD Anderson in which patients with B
cell malignancies receive Sleeping Beauty–derived CAR T cells after
stem cell or umbilical cord blood transplantation. She and her
colleagues reported in December at the American Society of Hematology
Annual Meeting that CAR T cells had been manufactured for 25 patients
and administered to 9 patients: 5 who had acute lymphocytic leukemia
and 4 who had non-Hodgkin lymphoma. Although it was too soon to tell
whether the CAR T cells would extend remissions, the researchers
reported that the treatment was well tolerated.

Looking ahead

Dr. Cooper said MD Anderson researchers and clinicians have started a
clinical study in which patients with B cell malignancies receive CAR T
cell treatment immediately after chemotherapy. This trial is led by
Chitra Hosing, M.D., a professor in the Department of Stem Cell
Transplantation and Cellular Therapy.

In all of the current studies of CAR T cells, researchers are observing
how long the modified T cells remain in the body. Dr. Kebriaei said
that future improvements in the persistence of the CAR T cells may
someday allow adoptive T cell transfer to replace stem cell
transplantation, which can be associated with significant side effects
and cost.

MD Anderson researchers are also hoping to use CAR T cells as another
treatment option for pediatric lymphoma patients, who generally have
fewer treatment options than adult patients. Dr. Cooper said, “Many
drug companies are not in a financial position to pay attention to
pediatric needs simply because there’s no return on investment for
them. But we may be able to use CAR T cells as drugs in this group of
vulnerable patients.”

For more
information, contactDr. Partow Kebriaei at 713-745-0663 or Dr. Laurence Cooper at 713-563-5393.